Age-related hearing loss (ARHL) is a serious public health issue: approximately one third of Americans between ages 65 and 74 and nearly half of those over age 75 have hearing loss. Incomplete understanding of the ARHL pathogenesis hampers development of effective preventive and treatment strategies. Ample evidence indicates that oxidative stress and associated mitochondrial dysfunction play essential roles in age-related neurodegenerative diseases and ARHL. We recently developed and characterized Fus1 KO mice that have profound changes in mitochondrial ROS production, calcium uptake, mitochondrial membrane potential (MMP), respiratory reserve, and mitochondrial fusion. These abnormal mitochondrial activities in Fus1 KO tissues lead to chronic oxidative stress, chronic inflammation, and premature aging. Our preliminary data provide ample evidence of premature age-related hearing loss in Fus1 KO mice. Using Auditory Brain Response (ABR) test we showed that while hearing of young (2 mo old) Fus1 KO mice is undistinguishable from WT mice, 9-12 mo old Fus1 KO mice exhibit profound hearing loss at all frequencies. Noteworthy, our preliminary data suggest that the ARHL pathology in Fus1 KO mice is the result of systemic chronic inflammation precipitated in older mice by chronic mitochondrial dysfunction and oxidative stress. We showed that chronic inflammation affects both bone marrow of the otic capsule and cochlear tissues. The goals of this proposal are 1) to perform a detailed subcellular and molecular characterization of damaging effects inflicted by mitochondrial dysfunction on different cochlear cells of Fus1 KO mice and 2) develop approaches to ameliorate and treat age-related hearing loss precipitated by oxidative stress and mitochondrial dysfunction. We will pursue these goals via two specific aims: Aim 1. Characterize dynamics and extent of mitochondrial, oxidative, and inflammatory damage in cochlea from young and aging Fus1 KO and WT mice; Aim 2. Compare anti-oxidant and anti-inflammatory effects of mitochondria- and cytoplasm-targeted ROS scavengers on dynamics of hearing loss in Fus1 KO mice. The results of this project will help to understand the mechanisms of the ARHL etiology providing a solid foundation for future use of Fus1 KO mice as a model of mitochondrial dysfunction-mediated ARHL. Also, this model will serve as a novel tool to develop ARHL preventive and therapeutic modalities for a large cohort of patients with systemic mitochondrial dysfunction, oxidative stress, chronic inflammation, and for aging individuals.